Diagnostic imaging and therapeutic radiopharmaceuticals play an important role in modern medicine. Many of the important radionuclides used in current applications are metals positioned in the main group or lanthanide series.1 This family of metals possesses diversity in nuclear and chemical properties that can be harnessed for both diagnostic and therapeutic applications. In nearly all cases, these metal ions are inherently toxic in a simple salt form and must be sequestered into an organic chelating compound (ligand) in order to render them biologically compatible. Furthermore, the ligand architecture is vitally important for creating a linking group for attachment to a biological targeting molecule.
Chelates are widely employed to isolate metal ions from environmental factors that would interfere with the intended use of the metal ions. This is commonly seen in the field of nuclear medicine, where radioactive isotopes of metals, i.e., radiometals, are used for molecular imaging and therapy due to their decay characteristics such as half-life and emission profile and due to their chemical properties such as lipophilicity and coordination behaviour.
Chelating agents for the main group and lanthanide metal ions have been the subject of intense fundamental and applied research for many years driven in part by advancements in medicine.2 For example, the emergence of magnetic resonance imaging (MRI) as a new diagnostic modality brought with it the need for paramagnetic metal-based contrast agents to enhance image quality, for this application gadolinium from the lanthanide series is preferred.3 As a result, there has been an exponential acceleration in the design and synthesis of new ligand systems that can hold up to the rigors of in vivo applications for MRI.4 Equally important is the fact that these same ligand systems are being recruited for other members of the lanthanide series (153Sm, 177Lu, 166Ho) and 90Y which possess highly desirable nuclear properties making them useful in radiopharmaceutical agents.5 The adaptability of similar ligands for all lanthanide ions is due to the very uniform and predictable properties intrinsic to the lanthanide series. The critical prerequisites of chelate complexes for metallic radioisotopes intended for human use is that they remain stable in the body (no dissociation of the metal) and that they can be prepared reasonably fast. This latter point is more applicable to nuclear applications where isotope half-life is a critical consideration in the formulation process. Chelate effectiveness is assessed in terms of thermodynamic stability and kinetic inertness. One often desirable property of chelates for biomedical applications is high thermodynamic stability. However, these ligand systems usually require longer reaction times and additional energy input is needed to form the final complex.
Gallium is a main group metal that comprises three radioactive isotopes useful in nuclear medicine. 66Ga is a positron-emitter with a half-life of 9.5 h; 67Ga, a gamma-emitter with a half-life of 3.26 d; 68Ga, a positron-emitter with a half-life of 68 min. Positron-emitters are useful for positron-emission tomography (PET) imaging; gamma-emitters, for single-photon-emission computed tomography (SPECT) imaging.
The chelates that are currently commonly used to bind gallium radiometals to biological targeting molecules are dominated by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and their derivatives. However, several studies have indicated that the conditions for the reactions of gallium with DOTA and NOTA could be improved by enabling formation of the coordination complexes in shorter times at ambient temperatures. These improvements are particularly critical to the widespread adoption of 68Ga as a radiometal of choice for nuclear medicine because of its relatively very short half-life of 68 min.
Chelates comprising picolinyl groups attached to a nitrogen atom6,7, ethylenediamine (en)8,9,10,11,12,13,14, cyclohexane-1,2-diamine15,16, and 1,4,7-triazacyclononane17,18,19,20,21 have been reported in the scientific literature and have been the subject of patent applications.22,23 These chelates have been designed to coordinate lanthanide ions, which are relatively large metal ions that in some instances possess large magnetic moments and are useful as magnetic-resonance-imaging contrast agents. Thus, the chelate comprising en has four picolinyl groups attached to each of the two en nitrogen atoms to give a decadentate (10-coordinate) chelate whereas the chelate comprising 1,4,7-triazacyclononane has three picolinyl groups attached one each to the three 1,4,7-triazacyclononane nitrogen atoms to give a nonadentate (9-coordinate) chelate. Classes of chelates comprising these particular chelates have been the subject of patent applications.
A chelate comprising two picolinyl groups attached one each to the two nitrogen atoms of en, hereafter called dedpa, and also of cyclohexane-1,2-diamine has been reported in the scientific literature24. Complexes of said chelate dedpa with the metal ions Zn2+, Cd2+, and Pb2+ were synthesized and found to comprise a hexadentate chelate bound to the metal ions to form an octahedral coordination environment. The present invention relates to chelates based on dedpa that can form complexes with radiometals useful in molecular imaging and therapy, more specifically for forming complexes with gallium radiometals for molecular imaging, because gallium radiometals prefer an octahedral coordination environment. An added advantage of using chelates based on dedpa for forming complexes with gallium radiometals is that gallium radiometals exist under physiological conditions as tripositive ions (Ga3+) that form stronger coordination complexes than Zn2+, Cd2+, or Pb2+ because of the increased charge of the ion.